Pancreatic islet transplantation is a therapeutic method useful for patients with insulin-dependent diabetes mellitus. Pancreas is constituted of exocrine glands and endocrine glands. Insulin which is only one hormone having the action of lowering blood glucose among hormones in the body is secreted from pancreatic islet β cells. Pancreatic islet transplantation intends to attain regeneration by replacement of the hypoglycemic system, by isolating this pancreatic islet from pancreas and transplanting the isolated islet into a patient with insulin-dependent diabetes mellitus.
Diabetes mellitus is roughly classified into two pathological conditions. In one pathological condition, pancreatic β cells are broken and damaged by some causes to lose secretion of insulin, while in the other pathological condition, insulin is present in blood at normal level or at higher level, however, the action of insulin is lowered because of the presence of insulin resistance in peripheral tissue. The former is called type 1 diabetes mellitus or juvenile-onset diabetes mellitus, and the latter is called type 2 diabetes mellitus. Pancreatic islet transplantation is applied to type 1 diabetes mellitus.
Type 1 diabetes mellitus develops by specific breakage of pancreatic β cells producing insulin, due to autoimmune abnormality. As the fundamental therapy thereof, pancreatic islet transplantation which is one of regeneration replacement therapies for pancreatic β cells is envisaged, however, the current pancreatic islet transplantation has a major problem of deficiency in the supply amount of islet. In general, it needs several years to ten-odd years to obtain the benefit of transplantation. Therefore, transplantation is not selected as a therapeutic method suggested for a patient with type 1 diabetes mellitus in regular clinical life.
Because of the above-described reason, it has been desired to produce cells having a function corresponding to that of pancreatic islet or pancreatic β cells. Also studies of stem cells recently rapidly making advances and attracting attention report a possibility of induction of the differentiation into pancreas endocrine cells (non-patent literatures 1 to 3). For supplying cells as an alternative to human mature pancreatic islet β cells, induction of the differentiation of embryonic stem cells (ES cells), tissue stem cells or human induced pluripotent stem cells (iPS cells) into insulin-secreting cells has attracted attention, and there have ever been a lot of reports.
ES cells are pluripotent stem cells derived from an inner cell cluster of blastocyst. It has been shown that if ES cells are cultured together with embryonic mesenchymal cells, ES cells advance toward the pancreatic and hepatic lineage. The present inventors have reported that by culturing ES cells on M15 cells as the supporting cell strain, induction of the differentiation thereof into liver with high efficiency becomes possible (non-patent literature 4). The present inventors have established a technology of induction of the highly-efficient differentiation of ES cells into embryonic endodermal respiratory and digestive organs by plane culture, by a method using supporting cells (patent literatures 1 and 2). Further, by use of M15 cells, ES cells can be induced in vitro with time into meso- and endoderm, embryonic endoderm and finally region specific embryonic endoderm-derived organs. M15 feeder cells are a tool useful for generating ES cell-derived lineage-specific cell type, belonging to three kinds of germ layers (neural ectoderm, mesoderm and embryonic endoderm) (non-patent literature 6). Further, the present inventors have reported a method of induction of the efficient differentiation of ES cells into pancreas and liver, utilizing M15 cells (patent literature 3). The above-described method is, however, a method utilizing live supporting cells, thus, when a small chemical compound exerting an influence on induction of the differentiation of ES cells is screened, an influence correlated to the supporting cells cannot be excluded and a target compound cannot be screened efficiently.